HZI Collection:http://hdl.handle.net/10033/108378
Tue, 03 Mar 2015 18:47:13 GMT2015-03-03T18:47:13ZComposing compound libraries for hit discovery--rationality-driven preselection or random choice by structural diversity?http://hdl.handle.net/10033/345823
Title: Composing compound libraries for hit discovery--rationality-driven preselection or random choice by structural diversity?
Authors: Weidel, Elisabeth; Negri, Matthias; Empting, Martin; Hinsberger, Stefan; Hartmann, Rolf W
Abstract: In order to identify new scaffolds for drug discovery, surface plasmon resonance is frequently used to screen structurally diverse libraries. Usually, hit rates are low and identification processes are time consuming. Hence, approaches which improve hit rates and, thus, reduce the library size are required.Wed, 01 Jan 2014 00:00:00 GMThttp://hdl.handle.net/10033/3458232014-01-01T00:00:00Z1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: a new class of potent and selective aldosterone synthase inhibitors.http://hdl.handle.net/10033/345291
Title: 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: a new class of potent and selective aldosterone synthase inhibitors.
Authors: Grombein, Cornelia M; Hu, Qingzhong; Heim, Ralf; Rau, Sabrina; Zimmer, Christina; Hartmann, Rolf W
Abstract: 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11β-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.Wed, 07 Jan 2015 00:00:00 GMThttp://hdl.handle.net/10033/3452912015-01-07T00:00:00ZMetabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors.http://hdl.handle.net/10033/345267
Title: Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors.
Authors: Gargano, Emanuele M; Perspicace, Enrico; Hanke, Nina; Carotti, Angelo; Marchais-Oberwinkler, Sandrine; Hartmann, Rolf W
Abstract: 17β-HSD2 is a promising new target for the treatment of osteoporosis. In this paper, a rational strategy to overcome the metabolic liability in the 2,5-thiophene amide class of 17β-HSD2 inhibitors is described, and the biological activity of the new inhibitors. Applying different strategies, as lowering the cLogP or modifying the structures of the molecules, compounds 27, 31 and 35 with strongly improved metabolic stability were obtained. For understanding biotransformation in the 2,5-thiophene amide class the main metabolic pathways of three properly selected compounds were elucidated.Mon, 24 Nov 2014 00:00:00 GMThttp://hdl.handle.net/10033/3452672014-11-24T00:00:00ZCatechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD.http://hdl.handle.net/10033/344574
Title: Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD.
Authors: Allegretta, Giuseppe; Weidel, Elisabeth; Empting, Martin; Hartmann, Rolf W
Abstract: A new strategy for treating Pseudomonas aeruginosa infections could be disrupting the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system. The goal is to impair communication among the cells and, hence, reduce the expression of virulence factors and the formation of biofilms. PqsD is an essential enzyme for the synthesis of PQS and shares some features with chalcone synthase (CHS2), an enzyme expressed in Medicago sativa. Both proteins are quite similar concerning the size of the active site, the catalytic residues and the electrostatic surface potential at the entrance of the substrate tunnel. Hence, we evaluated selected substrates of the vegetable enzyme as potential inhibitors of the bacterial protein. This similarity-guided approach led to the identification of a new class of PqsD inhibitors having a catechol structure as an essential feature for activity, a saturated linker with two or more carbons and an ester moiety bearing bulky substituents. The developed compounds showed PqsD inhibition with IC50 values in the single-digit micromolar range. The binding mode of these compounds was investigated by Surface Plasmon Resonance (SPR) experiments revealing that their interaction with the protein is not influenced by the presence of the anthranilic acid bound to active site cysteine. Importantly, some compounds reduced the signal molecule production in cellulo.Tue, 27 Jan 2015 00:00:00 GMThttp://hdl.handle.net/10033/3445742015-01-27T00:00:00Z